ABSTRACT Vascular health has emerged as one of the most important determinants of Alzheimer's disease and related dementias. Early adult and midlife cardiovascular disease (CVD) risk factors and subclinical disease may be important drivers of cognitive decline in midlife, a period that most likely is critical for influencing later life dementia risk. Yet, few studies have investigated early adulthood CVD risk exposures, including timing of exposure and whether subthreshold levels impact later life cognition. To accomplish these goals, we propose, to add cognitive testing to the Year 35 visit of the ongoing multisite Coronary Artery Risk Development in Young Adults (CARDIA) study. At baseline, CARDIA enrolled 5,115 black and white participants (mean age 24) who have been carefully followed for 30 years and had cognitive testing at visit years 25 and 30. Cognitive evaluation at Year 35 will allow us to determine 10-year cognitive change (mean age 50 to 60) at a critical time point when cognitive decline starts to diverge and potentially impacts late-life dementia risk. Our specific aims are: 1) To determine, using a life-course approach, the independent associations of 10-year midlife cognitive decline with timing, level (both subthreshold and threshold) and trend in CVD risk factors including body mass index, blood pressure, and fasting glucose, assessed over 35 years from early adult to midlife; 2) To determine the association of 10-year midlife cognitive decline with novel subclinical CVD markers over time including carotid artery intima thickness, coronary artery calcification and cardiac function; 3) To determine whether CVD risk factors and subclinical CVD markers are associated with brain aging indices in midlife, derived by the application of machine-learning neuroimaging pattern analysis to brain MRI and diffusion tensor imaging data obtained on nearly 700 CARDIA participants at midlife; Exploratory) To assess black/white disparities in 10- year cognitive decline and determine the extent to which such disparities are explained by burden of CVD risk. Guided by strong preliminary data, our main hypothesis is that CVD risk factors begin to exert influence as early as the third decade of life and that subthreshold levels (eg systolic blood pressure ?120 mm) are important drivers for this. In addition, we hypothesize that subclinical CVD measures (especially cardiac function and atherosclerosis) are associated with greater decline in midlife cognition and accelerated brain aging. No other study in the US has such comprehensive data on a wide array of early adult CVD risk factors that may influence cognitive aging. As an experienced multidisciplinary team using innovative statistical methods to analyze essentially unique longitudinal data on early adult and midlife CVD risk factors and subclinical disease, we have the opportunity to investigate the associations of these life-course exposures with cognitive decline and brain health in midlife. Identifying dementia risk factors early in the life-course may lead to interventions to help maintain healthy brain aging and prevent the onset of dementia.